This invention relates to novel inhibitors of sex steroid activity such as antiestrogen compounds having effective antagonistic capability while substantially lacking agonistic effects. More particularly, certain preferred embodiments of the invention relate to certain estradiol and diphenylethylene analogs which have high affinity for estrogen receptors but do not activate such receptors and/or which inhibit the production of sex steroids or their precursors.
During the treatment of certain sex steroid-dependent diseases, it is important to greatly reduce or, if possible, eliminate certain sex steroid-induced effects. For this purpose, it is desirable both to block receptor sites stimulated by sex steroids and also to reduce the amount of sex steroid available to act at these sites. For example, alternative or concurrent therapy to administration of antiestrogens could involve attempts to block the production of estrogens (e.g. by ovariectomy) such that less is available to activate receptor sites. However, prior art methods for blocking estrogen production insufficiently inhibit estrogen-induced functions. Indeed, it is possible that even in the total absence of sex steroid, some receptors may be activated. See Simard and Labrie, "Keoxifene shows pure antiestrogenic activity in pituitary gonadotrophs", Mol. Cell. Endocrinol. 39: 141-144, (1985), especially page 144.
Hence, antagonists of sex steroids may produce greater therapeutic results than therapy which only inhibits sex steroid production. Prior art antagonists, however, often have insufficient affinity for receptors, and some, although capable of binding the receptors, may themselves act as agonists and undesirably activate the very receptors they are intended to shield from activation.
There is, therefore, a need in the art for antiestrogens which effectively block estrogen receptors with minimal or no agonistic effect. In Wakeling and Bowler, "Steroidal Pure Antioestrogens", J. Endocrinol. 112:R7-R10 (1987), a steroid derivative is said to act as an antiestrogen but to exhibit some estrogen activity. The net effectiveness of a compound is effected by both its agonistic (undesirable) and antagonistic (desirable) activities.
In U.S. Pat. No. 4,094,994, it is disclosed that the use of certain antiestrogens may inhibit certain human breast tumor cells.
H. Mouridsen et al., Cancer Treatm. Rev. 5: 131-141 (1978), discloses that Tamoxifen, an antiestrogen, is effective in remission of advanced breast cancer in about 30 percent of the women patients treated.
The combined use of the antiestrogen Tamoxifen and a luteinizing hormone-releasing hormone agonist, Buserelin, is also known for treatment of breast cancer. See, for instance, Klijn et al. J. Steroid Biochem. 420: no. 6B, 1381 (1984). The objective remission of such cancers, however, remains unacceptably low.
It has been found that certain 7.alpha.-substituted derivatives of estradiol, for example a 7.alpha.-(CH.sub.2).sub.10 CONMeBu substitution possess antiestrogenic activity (Bowler et al., 1985; Eur. Patent Application 0138504; Wakeling and Bowler, J. Steroid Biochem. 30: 141-147 (1988). See also U.S. Pat. No. 4,659,516. The substitution (CH.sub.2).sub.9 SOC.sub.5 H.sub.6 F.sub.5 has also been used on certain compounds (Wakeling et al., Cancer Res. 51: 3867-3873, 1991).
Certain --(CH.sub.2).sub.10 CONMeBu substituted compounds are also disclused in U.S. Pat. No. 4,732,912 (See e.g. example 5 and 16). See also EP Pat. No. 166 509, EP Pat No. 124 369, EP Pat. No. 160 508, EP Pat. No. 163 416, U.S. Pat. No. 4,760,061, U.S. Pat. No. 4,751,240 and Wakeling A. E. and Bowler, J., J. Endocrinol. 112: R7-R10 (1987).
Estradiol derivatives bearing a carboxyalkyl substituent at the 7.alpha.-position maintained their affinity for the estrogen receptor when linked via their carboxy group to agarose or polyacrylamide resin for affinity chromatography purification of the estrogen receptor (Bucourt et al., J. Biol. Chem. 253: 8221, 1978).
Some steroid derivatives, such as 16-methylene estradiol and 16-methylene estrone, have been described as inhibitors of 17.beta.-hydroxysteroid dehydrogenase activity (Thomas et al., J. Biol. Chem. 258: 11500, 1983).
Certain nonsteroidal compounds which are stated to have antiandrogenic effect are described by Furr et al., J. Endocrinol. 113: R7-R9 (1987).
U.S. Pat. No. 4,659,695 relates to a method of treatment of prostate cancer for susceptible male animals including humans whose testicular hormonal secretions are blocked by surgical or chemical means, e.g., by use of an LHRH agonist, e.g., [D-Trp.sup.6, des-Gly-NH.sub.2.sup.10 ]LHRH ethylamide. The treatment includes administering an antiandrogen, e.g., flutamide in association with at least one inhibitor of sex steroid biosynthesis, e.g., aminoglutethimide and/or ketoconazole. See also PCT/U.S. 85/01454 (International Publication Number WO 86/01105) regarding combination therapy for treating hormonal-dependent cancers.
U.S. Pat. No. 4,472,382 relates to a method of treating prostate cancer using the combination of an antiandrogen and an LHRH agonist.
In U.S. Pat. No. 4,386,080 relates to new amide derivatives, and more particularly to novel acylanilides, possessing antiandrogenic properties.
In French Patent 2528434 and in Jordan and Koch, "Regulation of Prolactin Synthesis in vitro by estrogenic and antiestrogenic derivatives of estradiol and Estrone", Endocrinology 124(4): 1717-1725 (1989), antiestrogenic effects are described for certain 11.beta.-substituted estradiol derivatives.
In U.S. Pat. No. 3,995,060, U.S. Pat. No. 4,161,540 and U.S. Pat. No. 4,139,638, it is disclosed that certain 4'-substituted and 3'-,4'-disubstituted anilides have antiandrogenic properties.
For a number of years, researchers have attempted to develop compounds which can efficiently inhibit androgen and/or estrogen formation without causing adverse effects to healthy tissues. More particularly, the inhibition of 17.beta.-hydroxysteroid dehydrogenase, which is involved in the biosynthesis of testosterone, androst-5-ene-3.beta.,17.beta.-diol and estradiol, has been studied by some workers. Some affinity-label inhibitors for human placental estradiol 17.beta.-dehydrogenase have been described (C. C. Chin and J. C. Warren, J. Biol. Chem. 250: 7682-7686, 1975; Y. M. Bhatnagar et al., J. Biol. Chem. 253: 811-815, 1978; C. C. Chin et al., J. Biol. Chem. 255: 3660-3664, 1980; J. L. Thomas and R. C. Strickler, J. Biol. Chem. 258: 1587-1590, 1983).
B. Tobias et al., J. Biol. Chem. 257: 2783-2786 (1982) and R. J. Auchus and D. F. Covey, Biochemistry 25: 7295-7300 (1986) disclose, respectively, the use of 17.beta.-propynyl-substituted progestins and propynyl-substituted 3-hydroxy-14,15-secoestra-1,3,5(10)-trien-17-one as inhibitors of the 17.beta.-estradiol dehydrogenase.
Thomas J. L. et al., J. Biol. Chem. 258: 11500 (1983) have described that 16-methylene estradiol and 16-methylene estrone are inhibitors of 17.beta.-hydroxysteroid dehydrogenase activity.
Prior art methods have not been completely effective in inhibiting sex steroid synthesis while avoiding undesirable side effects.
Von Angerer et al. discuss other antiestrogens in "1-(aminoalkyl)-2-phenylindoles as Novel Pure Estrogen Antagonists", J. Med. Chem. 1990; 33: 2635-2640. In U.S. Pat. No. 4,094,994, where it is said that the use of certain antiestrogens inhibit certain human breast tumor cells. See also DE 3821148.
A. Saeed et al., J. Med. Chem. 33: 3210-3216, 1990; A. P. Sharma et al., J. Med. Chem. 33: 3216-3222 and 3222-3229 (1990) described the synthesis and biological activities of 2,3-diaryl-2H-1-benzopyrans analogs as antiestrogens having the following molecular structure: ##STR2##
N. Durani et al., J. Med. Chem. 32: 1700-1707 (1989) describe the synthesis and biological activities of benzofuran and triarylfuran analogues as antiestrogens.
The European counterpart of priority applications 07/377,010 and 07/265,150 was published on May 9, 1990 as European Application No 0367576. The European Search report for that case disclosed the following publications:
In E.P. Patent No 305 242, Nique et al relates to the synthesis and the use of 17-acyl steroids as drugs. The Search Report emphasized page 7, compound I'C.
In E.P. Patent No 280 618, Nique et al. relates to 7-substituted 19-nor-steroids for drugs. The Search Report emphasized Examples 2, 3, pages 22, 23 and the claims.
In D.E. Patent No 32 42 894 A1, Neef et al relates to 17.alpha.-substituted equilenin for inhibition of progesterone biosynthesis and control of the fertility.
In U.S. Pat. No 2,875,199, Cella, J. A. discuss 17-carboxylated estradiols for decreasing the serum concentration of cholesterol.
Blickenstaff et al. (Steroids, Vol. 46, No 4 et 5, pages 889-902) described the synthesis of 16 and 17-substituted estradiols suitable for coupling to vinblastine species.
Other Search Report References were previously discussed herein.